Cluster-Randomized, Crossover Trial of Head Positioning in Acute Stroke.

BACKGROUND: The role of supine positioning after acute stroke in improving cerebral blood flow and the countervailing risk of aspiration pneumonia have led to variation in head positioning in clinical practice. We wanted to determine whether outcomes in patients with acute ischemic stroke could be improved by positioning the patient to be lying flat (i.e., fully supine with the back horizontal and the face upwards) during treatment to increase cerebral perfusion. METHODS: In a pragmatic, cluster-randomized, crossover trial conducted in nine countries, we assigned 11,093 patients with acute stroke (85% of the strokes were ischemic) to receive care in either a lying-flat position or a sitting-up position with the head elevated to at least 30 degrees, according to the randomization assignment of the hospital to which they were admitted; the designated position was initiated soon after hospital admission and was maintained for 24 hours. The primary outcome was degree of disability at 90 days, as assessed with the use of the modified Rankin scale (scores range from 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death). RESULTS: The median interval between the onset of stroke symptoms and the initiation of the assigned position was 14 hours (interquartile range, 5 to 35). Patients in the lying-flat group were less likely than patients in the sitting-up group to maintain the position for 24 hours (87% vs. 95%, P<0.001). In a proportional-odds model, there was no significant shift in the distribution of 90-day disability outcomes on the global modified Rankin scale between patients in the lying-flat group and patients in the sitting-up group (unadjusted odds ratio for a difference in the distribution of scores on the modified Rankin scale in the lying-flat group, 1.01; 95% confidence interval, 0.92 to 1.10; P=0.84). Mortality within 90 days was 7.3% among the patients in the lying-flat group and 7.4% among the patients in the sitting-up group (P=0.83). There were no significant between-group differences in the rates of serious adverse events, including pneumonia. CONCLUSIONS: Disability outcomes after acute stroke did not differ significantly between patients assigned to a lying-flat position for 24 hours and patients assigned to a sitting-up position with the head elevated to at least 30 degrees for 24 hours. (Funded by the National Health and Medical Research Council of Australia; HeadPoST ClinicalTrials.gov number, NCT02162017 .).

Statins and the risk of bleeding in patients taking dabigatran.

OBJECTIVES: Dabigatran etexilate is a direct thrombin inhibitor that clinicians increasingly prescribe to prevent stroke in patients with non-valvular atrial fibrillation (NVAF). Clinicians also commonly prescribe statins for primary and secondary prevention of cardiovascular diseases. Little is known about the bleeding risk in patients taking a statin and dabigatran together. The aim of this study was to evaluate the safety and persistence of dabigatran after co-medication with statins. MATERIALS AND METHODS: We performed a prospective, multicenter registry study of stroke patients with NVAF who initiated dabigatran therapy within 3 months after a clinically evident ischemic cerebrovascular event between 2013 and 2017. The main outcome measure was symptomatic bleeding after 90, 180, and 360 days. RESULTS: In total, 652 patients (336 statin users, 316 non-users) were followed for 1 year after dabigatran therapy. Cox multivariate analysis demonstrated that male sex, prior use of aspirin, and concurrent use of an antiarrhythmic drug were associated with a higher risk of bleeding at 360 days. After adjusting time-dependent covariates, statin users had a significantly lower bleeding risk (adjusted hazard ratio: 0.11, P < 0.001) than non-users. Kaplan-Meier analysis indicated that patients prescribed with statins had a higher rate of bleeding-free survival (P = 0.028). CONCLUSION: For secondary prevention of stroke in patients with NVAF who are taking dabigatran etexilate, co-prescription with a statin was associated with a lower risk of bleeding complications. Future research is needed to determine the pharmacological mechanism underlying this effect.

MicroRNA let-7g possesses a therapeutic potential for peripheral artery disease.

Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis and conveys a significant health burden globally. Critical limb ischaemia encompasses the most severe consequence of PAD. Our previous studies indicate that microRNA let-7g prevents atherosclerosis and improves endothelial functions. This study aimed to investigate whether and how let-7g therapy may improve blood flow to ischaemic limbs. The present study shows that let-7g has multiple pro-angiogenic effects on mouse ischaemic limb model and could be a potential therapeutic agent for PAD. Mice receiving intramuscular injection of let-7g had more neovascularization, better local perfusion and increased recruitment of endothelial progenitor cells after hindlimb ischaemia. The therapeutic effects of let-7g's on angiogenesis are mediated by multiple regulatory machinery. First, let-7g increased expression of vascular endothelial growth factor-A (VEGF-A) and VEGF receptor-2 (VEGFR-2) through targeting their upstream regulators HIF-3α and TP53. In addition, let-7g affected the splicing factor SC35 which subsequently enhanced the alternative splicing of VEGF-A from the anti-angiogenic isoform VEGF-A165b towards the pro-angiogenic isoform VEGF-A164a . The pleiotropic effects of let-7g on angiogenesis imply that let-7g may possess a therapeutic potential in ischaemic diseases.

Cholesterol Levels Are Associated with 30-day Mortality from Ischemic Stroke in Dialysis Patients.

BACKGROUND: We investigated the impact of serum cholesterol levels on 30-day mortality after ischemic stroke in dialysis patients. METHODS: From the Taiwan Stroke Registry data, we identified 46,770 ischemic stroke cases, including 1101 dialysis patients and 45,669 nondialysis patients from 2006 to 2013. RESULTS: Overall, the 30-day mortality was 1.46-fold greater in the dialysis group than in the nondialysis group (1.75 versus 1.20 per 1000 person-days). The mortality rates were 1.64, .62, 2.82, and 2.23 per 1000 person-days in dialysis patients with serum total cholesterol levels of <120 mg/dL, 120-159 mg/dL, 160-199 mg/dL, and ≥200 mg/dL, respectively. Compared to dialysis patients with serum total cholesterol levels of 120-159 mg/dL, the corresponding adjusted hazard ratios of mortality were 4.20 (95% confidence interval [CI] = 1.01-17.4), 8.06 (95% CI = 2.02-32.2), and 6.89 (95% CI = 1.59-29.8) for those with cholesterol levels of <120 mg/dL, 160-199 mg/dL, and ≥200 mg/dL, respectively. CONCLUSIONS: Dialysis patients with serum total cholesterol levels of ≥160 mg/dL or <120 mg/dL on admission are at an elevated hazard of 30-day mortality after ischemic stroke.

Clinical implication of hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator.

To determine the clinical implications of hemorrhagic transformation (HT) after thrombolysis, 241 eligible patients receiving alteplase for acute ischemic stroke were studied. HT was classified, according to the European Cooperative Acute Stroke Study criteria, as hemorrhagic infarction (HI) or parenchymal hemorrhage (PH). Symptomatic intracranial hemorrhage (SICH) was defined according to the National Institute of Neurological Disorders and Stroke study. A novel classification, clinically significant intracranial hemorrhage (CSICH) was defined as HTs associated with an unfavorable clinical outcome (modified Rankin Scale 5-6) at 3 months. For all subtypes of HT, we found that patients receiving alteplase were more often in the standard-dose group (0.90 ± 0.02 mg/kg) than in the lower dose group (0.72 ± 0.07 mg/kg). PH and SICH were related to an unfavorable clinical outcome, while HI was not. There was a positive trend between age and CSICH in patients receiving the standard dose (P = 0.0101), and between alteplase dose and CSICH in patients ≥70 years old (P = 0.0228). All PHs (including asymptomatic PHs) and symptomatic HIs have been found to be associated with unfavorable outcome, and for this reason defined as CSICH. Independent predictors of CSICH were age ≥70 years and the standard dose of alteplase. Further studies of thrombolysis for ischemic stroke with different doses of alteplase are warranted.

Lack of association between a functional variant of the BRCA-1 related associated protein (BRAP) gene and ischemic stroke.

BACKGROUND: Atherosclerosis shares common pathogenic features with myocardial infarction (MI) and ischemic stroke. BRCA-1 associated protein (BRAP), a newly identified risk gene for MI, aggravates the inflammatory response in atherosclerosis. The aim of this study was to test the association between the BRAP gene and stroke in a Taiwanese population. METHODS: A total of 1,074 stroke patients and 1,936 controls were genotyped for the functional SNP rs11066001. In our previous studies, the rare allele of this SNP has been repeatedly shown to exert a recessive effect. Therefore, in the current study, we tested for the same recessive model. First, the genotype distributions between all the controls and all the stroke cases were compared. Then to reduce heterogeneity, we explored several population subsets by selecting young stroke subjects (using 45 years of age as the cutoff point), age- and sex-comparable controls, plaque-free controls, and stroke subtypes. RESULTS: We did not find any significant association for the entire data set (OR = 0.94, p = 0.74) or for the subset analyses using age- and sex-comparable controls (p = 0.70) and plaque-free controls (p = 0.91). Analyses of the four stroke subtypes also failed to show any significant associations (p = 0.42 - 0.98). For both young and old subjects, the GG genotype of rs11066001 was similar in the stroke cases and unmatched controls (8.1% vs. 9.4% in young subjects and 8.0% vs. 7.8% in old subjects). Comparing stroke cases with plaque-free controls also failed to find any significant association. CONCLUSIONS: The BRAP polymorphism may not play an important role in ischemic stroke in the studied population.

Serum microRNA-21 and microRNA-221 as potential biomarkers for cerebrovascular disease.

BACKGROUND/AIMS: MicroRNA miR-21, miR-221 and miR-145 have been implicated in the cardiovascular system. We aimed to compare the serum levels of the three microRNAs (miRNAs) in different severities of cerebrovascular diseases and evaluate the feasibility of using these miRNAs as biomarkers for stroke. METHODS: We enrolled 167 subjects with ischemic stroke, 66 atherosclerosis subjects with any carotid plaque score and 157 healthy controls. These three types of subjects represent three levels of severity in cerebrovascular diseases. Analysis of covariance was used to evaluate the relationship between miRNAs and disease severity with adjustment for conventional risk factors. To test the prediction for stroke, we built regression models containing the serum miRNA levels and risk factors. Prediction capabilities were compared by the receiver operating characteristic curves. RESULTS: Stroke patients and atherosclerosis subjects had significantly higher miR-21 and lower miR-221 serum levels than healthy controls, while the miR-145 expression was too low to provide useful information in this regard. The best model showed that miR-21 and miR-221 were independent predictors. There was a 6.2-fold increase for stroke risk when miR-21 levels increase by log102(-ΔCt) = 1, while a 10.4-fold increase was observed as miR-221 decreases by log102(-ΔCt) = 1. CONCLUSIONS: Serum miR-145 was not detected in over 50% of the patients and it may not be an ideal marker to predict stroke. MiR-21 and miR-221 are novel biomarkers for atherosclerosis and stroke.

Predictors of in-hospital mortality and prognosis in patients with large hemispheric stroke receiving decompressive craniectomy.

OBJECTIVE: Decompressive craniectomy reduces fatality in patients with space-occupying infarctions. However, mortality remains high. We aimed to identify predictors of in-hospital mortality and outcomes in a cohort of patients with large hemispheric stroke receiving decompressive craniectomy. METHODS: We retrospectively reviewed all patients diagnosed with complete middle cerebral artery infarction and receiving decompressive craniectomy. Hospital characteristics were compared among different groups (survivors versus non-survivors, good outcome versus poor outcome). A total of 71 consecutive patients were enrolled. RESULTS: From 2004 January to 2010 April, 71 patients were enrolled whose mean age was 65.11 ± 13.13 years and 33 (46.5%) of these were men. The in-hospital mortality was 28.2% overall. Of the patients who survived and were discharged, 37 (77.1%) had poor outcome (mRS 4-6) and 11 (22.9%) had good outcome (mRS 0-3). Pre-operation brain computed tomography (CT) hypodensity volume (p = 0.001) was significantly associated with mortality. In binary logistic regression model, pre-operation brain CT hypodensity volume (OR = 1.015; 95% CI, 1.001 to 1.030) and age (OR = 1.112; 95% CI, 1.017 to 1.215) were both significantly associated with outcomes. CONCLUSIONS: In patients with large hemispheric stroke receiving decompressive craniectomy, pre-operation brain CT hypodensity volume was significantly associated with in-hospital mortality whereas age was not. Pre-operation brain CT hypodensity volume and age were predictors of outcomes in those who survived the acute phase.

10th Anniversary of the Asia Pacific Stroke Organization: State of Stroke Care and Stroke Research in the Asia-Pacific.

The Asia Pacific Stroke Organization is the largest international and professional stroke group in the region. It has worked consistently over the last 10 years to gain visibility and consistency across the Asia-Pacific and beyond. The 10-year journey will be reviewed in the background of many internal and external developments including changes in Asia-Pacific stroke epidemiology, stroke care systems, and stroke service developments as well as major research studies in the Asia-Pacific.

Get With the Guidelines-Stroke performance indicators: surveillance of stroke care in the Taiwan Stroke Registry: Get With the Guidelines-Stroke in Taiwan.

BACKGROUND: Stroke is a leading cause of death around the world. Improving the quality of stroke care is a global priority, despite the diverse healthcare economies across nations. The American Heart Association/American Stroke Association Get With the Guidelines-Stroke program (GWTG-Stroke) has improved the quality of stroke care in 790 US academic and community hospitals, with broad implications for the rest of the country. The generalizability of GWTG-Stroke across national and economic boundaries remains to be tested. The Taiwan Stroke Registry, with 30 599 stroke admissions between 2006 and 2008, was used to assess the applicability of GWTG-Stroke in Taiwan, which spends ≈ 1/10 of what the United States does in medical costs per new or recurrent stroke. METHODS AND RESULTS: Taiwan Stroke Registry, sponsored by the Taiwan Department of Health, engages 39 academic and community hospitals and covers the entire country with 4 steps of quality control to ensure the reliability of entered data. Five GWTG-Stroke performance measures and 1 safety indicator are applicable to assess Taiwan Stroke Registry quality of stroke care. Demographic and outcome figures are comparable between GWTG-Stroke and Taiwan Stroke Registry. Two indicators (early and discharge antithrombotics) are close to GWTG-Stroke standards, while 3 other indicators (intravenous tissue plasminogen activator, anticoagulation for atrial fibrillation, lipid-lowering medication) and 1 safety indicator fall behind. Preliminary analysis shows that compliance with selected GWTG-Stroke guidelines is associated with better outcomes. CONCLUSIONS: Results suggest that GWTG-Stroke performance measures, with modification for ethnic factors, can become global standards across national and economic boundaries for assessing and improving quality of stroke care and outcomes. GWTG-Stroke can be incorporated into ongoing stroke registries across nations.

Cerebral white matter hyperintensities predict functional stroke outcome.

BACKGROUND: Growing evidence suggests that white matter hyperintensities (WMHs) are implicated in stroke recurrence and mortality, and their location can be a critical factor. This study evaluated the impact of periventricular WMHs (PVWMHs) and subcortical WMHs (SWMHs) on poststroke functional outcomes. METHODS: Brain MRI was performed on 187 acute ischemic stroke patients (57.8% male; mean age = 64.3 years) recruited from the Kaohsiung Municipal Hsiao-Kang Hospital from February 2007 to January 2008. A Fazekas score >or=2 in the periventrcular or subcortical white matter was taken as presence of WMHs. Demographic data and risk factors for stroke were assessed. Functional stroke outcomes were evaluated 30 days after stroke using the Barthel Index (BI) and the modifiedRankin Scale (mRS). RESULTS: WMHs were inversely linked to favorable functional outcome measured by mRS (p = 0.001) and BI (p = 0.003). Evaluating different locations, PVWMHs were associated with unfavorable functional outcomes (p = 0.002, mRS; p = 0.001, BI). SWMHs were related to mRS (p = 0.026) but not BI (p = 0.069). After controlling other stroke risk factors, infarct volumes and initial stroke severity, PVWMHs were a significant indicator for both mRS (OR = 2.76; 95% CI = 1.03-7.40) and BI (OR = 3.07; 95% CI = 1.13-8.40), but SWMHs were not. CONCLUSIONS: Unfavorable functional stroke outcome is associated with MRI WMHs. In terms of location, PVWMHs but not SWMHs are related to functional stroke outcome.

Immediate effects of noxious and innocuous thermal stimulation on brain activation in patients with stroke.

Case-control studies have shown that noxious thermal stimulation (TS) can improve arm function in patients with stroke. However, the neural mechanisms underlying this improvement are largely unknown. We explored functional neural activation due to noxious and innocuous TS intervention applied to the paretic arm of patients with stroke. Sixteen participants with unilateral cortical infarctions were allocated to one of two groups: noxious TS (8 patients; temperature combination: hot pain 46°C to 47°C, cold pain 7°C-8°C) or innocuous TS (n = 8; temperature combination: hot 40°C-41°C, cold 20°C-21°C). All subjects underwent fMRI scanning before and after 30 min TS intervention and performed a finger tapping task with the affected hand. Immediate brain activation effects were assessed according to thermal type (noxious vs. innocuous TS) and time (pre-TS vs post-TS). Regions activated by noxious TS relative to innocuous TS (P < .05, adjusted for multiple comparisons) were related to motor performance and sensory function in the bilateral primary somatosensory cortices, anterior cingulate cortex, insula, thalamus, hippocampus and unilateral primary motor cortex, secondary somatosensory cortex at the contralateral side of lesion, and unilateral supplementary motor area at the ipsilateral side of lesion. Greater activation responses were observed in the side contralateral to the lesion, suggesting a significant intervention effect. Our preliminary findings suggest that noxious TS may induce neuroplastic changes unconstrained to the local area.Trial registration: NCT01418404.

Low Cholesterol Levels Increase Symptomatic Intracranial Hemorrhage Rates After Intravenous Thrombolysis: A Multicenter Cohort Validation Study.

AIM: Although a lower level of non-high-density lipoprotein cholesterol (HDL-C) was reported to be inversely associated with spontaneous intracranial hemorrhage (ICH), no enough evidence has verified whether lipid profiles modify hemorrhagic transformation and functional outcomes in patients with acute ischemic treated with thrombolysis. METHODS: This multicenter cohort study included 2373 patients with acute ischemic stroke treated with intravenous thrombolysis between December 2004 and December 2016. Of these, 1845 patients were categorized into either the hyperlipidemia or non-hyperlipidemia group. Symptomatic ICH (SICH) rates within 24-36 h of thrombolytic onset and functional outcomes at 30 and 90 days were longitudinally surveyed. Models of predicting hemorrhagic transformation were used to validate our findings. RESULTS: For enrolled 1845 patients, SICH rates were ≥2-fold reduced for the hyperlipidemia group by the NINDS (adjusted RR: 0.488 [0.281-0.846], p=0.0106), the ECASS II (adjusted RR: 0.318 [0.130-0.776], p=0.0119), and SITS-MOST standards (adjusted RR: 0.214 [0.048-0.957], p=0.0437). The favorable functional rates between the two groups were not significantly different. Lower levels of LDL-C were showed in robust association with SICH. With a cut-off LDL-C value of ＜130 mg/dL, new models are more robust and significant in predicting hemorrhagic transformation within 24-36 h. CONCLUSIONS: This study supports the strong association between reduced LDL-C and increased SICH, but not for functional outcomes in patients with acute ischemic stroke treated with intravenous thrombolysis. LDL-C level of ＜130 mg/dL is supposed to a candidate marker for predicting SICH within 24-36 h.

Low-dose versus standard-dose intravenous alteplase for octogenerian acute ischemic stroke patients: A multicenter prospective cohort study.

BACKGROUND AND PURPOSE: The optimal dose of alteplase for acute ischemic stroke among geriatric patients is unclear. We aimed to assess the efficacy and safety of a low-dose (0.6 mg/kg) and standard-dose (0.9 mg/kg) alteplase for varying severity of Asian geriatric stroke patients. METHODS: The favorable functional outcome on day 90 after stroke onset, and the symptomatic intracranial hemorrhage (SICH) rate following 24-36 h of intravenous alteplase were measured. The baseline NIHSS of 4-8, 9-13, ≥14 were defined as mild, moderate, and high severity, respectively. RESULTS: Totally, 249 geriatric patients treated with low-dose (n = 108) and standard-dose (n = 141) alteplase. Compared to standard-dose alteplase, low-dose alteplase had decrease in favorable functional outcome (22.2% versus 34.8%), and no difference in SICH rates was observed. For mild severity patients, the mortality was significantly increased with standard-dose alteplase (the NNT/NNH = 22.9/8.0 for mild severity, the NNT/ NNH = 15.0/14.7 for moderate severity, and the NNT/NNH = 13.5/19.6 for high severity). CONCLUSIONS: Standard-dose and low-dose alteplase were comparable in reducing major disability, but low-dose alteplase for mild stroke showed much reduced mortality on day 90 for octogenarians.

Behcet's disease with involvement of major arteries: a case report.

Vascular involvement is not infrequent in Behcet's disease (BD). It is generally seen in the form of superficial thrombophlebitis or occlusion of major veins. In rare instances, arterial occlusion and aneurysm formation may be seen in BD. We reported a young male with BD, diagnosed at the age of twenty for relapsing and remitting oral ulceration, skin rash, arthralgia and ocular painful redness for three years. At the age of 21, he had recurrent abdominal aortic aneurysm and inconspicuous neurological manifestations including dizziness, tinnitus and transients of blurred vision. The carotid angiography disclosed the occlusion of bilateral common carotid arteries (CCA). A carotid endarterectomy was subsequently performed to reduce the risk of stroke. The pathological examination of the occluded segment of CCA revealed chronic inflammation, which was attributable to BD. There was no atherosclerotic change. To the best of our knowledge, this is the first case report of concurrent bilateral CCA occlusion and relapsing abdominal aortic aneurysm. Even in the absence of specific neurological symptoms, we suggest that cerebrovascular investigation need to take into consideration in BD patients with unexplained cranial symptoms.

Simultaneous thrombosis of cerebral artery and venous sinus.

Cerebral venous thrombosis (CVT) is infrequent among cerebrovascular diseases. The simultaneous thrombosis involving both cerebral artery and venous sinus is even extremely rare. We reported a 41-year-old woman who presented with acute headache and left hemiparesis due to concomitant arterial ischemic stroke and recurrent CVT. Extensive investigation disclosed acquired protein C and protein S deficiency, iron deficiency anemia (IDA) and cryoglobulinemia. She was treated with intravenous injection of heparin followed by oral anticoagulant therapy. The headache rapidly subsided; however, left hemiparesis persisted over five months. The rare condition of simultaneous thrombosis of cerebral artery and venous sinus may be caused by the synergistic effect of coagulation disorders, IDA and cryoglobulinemia.

Potential risk and protective factors for in-hospital mortality in hyperacute ischemic stroke patients.

In the era of thrombolytic therapy for hyperacute ischemic stroke, most investigators have focused their attention on the factors influencing mortality and functional outcomes in patients treated with thrombolysis, but very few have focused on these factors among patients not receiving thrombolysis. The aim of this study was to investigate the prognostic factors for mortality in all hyperacute stroke patients with or without thrombolysis. In 2005, we enrolled 101 ischemic stroke patients (43 females, 58 males; mean age, 68 years) who were transported to the emergency department (ED) within 4 hours of symptom onset. The overall in-hospital mortality rate was 17.8% (18/101). According to t test analysis, age (p = 0.034), time interval from neurologist consultation (p < 0.0001) and ED to ward admission (p = 0.001), Glasgow coma scale (GCS) (p = 0.001), National Institutes of Health Stroke Scale (NIHSS) (p < 0.0001) and the sum of major risk factors of cerebrovascular disease (CVD) (p < 0.0001) were significantly different between mortality and survivor groups. Further Chi-squared test analysis revealed significant differences in the presenting consciousness disturbance (p = 0.001), place of attack (p = 0.04), and referral transportation (p = 0.008) between these groups. In conclusion, old age, delay between neurologist consultation and ward admission, severity of stroke, and multiple risk factors of CVD are significant risk factors for in-hospital mortality. Conversely, being free of initial consciousness disturbance, living in an urban area, and having direct transportation to a stroke center are protective factors in survivors. The concept of "brain attack" should be re-emphasized among ED physicians. The interconnection between stroke centers and emergency medical systems (EMS) should be more tightly built to promote timely management for hyperacute stroke care.